title: BCR-ABL activates pathways mediating cytokine independence and protection against apoptosis in murine hematopoietic cells in a dose-dependent manner.
abstract: The hallmark of chronic myeloid leukemia (CML) is the chimeric tyrosine kinase oncogene bcr-abl. Since expression of bcr-abl mRNA frequently increases with disease progression and a duplication of the Philadelphia chromosome (harbouring the bcr-abl hybrid locus) represents the most frequent karyotypic abnormality in acute phase CML, we hypothesized that the level of BCR-ABL protein may affect the disease phenotype. Therefore, the biological effects of high and low levels of BCR-ABL expression were compared in growth factor-dependent and -independent myeloid and lymphoid cell lines. Our results demonstrated that low levels of BCR - ABL were sufficient to render these cell lines growth factor independent and tumorigenic, but higher levels were mandatory for additional protection against apoptotic stimuli. The provision of growth factor or an activated ras oncogene did not afford the same degree of protection as high levels of BCR-ABL and there were qualitative differences between the survival signals mediated by BCR-ABL and Bcl-2. These results have enabled us to establish a dose-dependent hierarchy of BCR-ABL induced biological effects, thus distinguishing the activation of pathways mediating protection from cytokine withdrawal from those protecting against other apoptotic stimuli.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, PO Royal Melbourne Hospital, Victoria, Australia.
authors.forename: N
authors.initials: N
authors.lastname: Cambier
authors.forename: R
authors.initials: R
authors.lastname: Chopra
authors.forename: A
authors.initials: A
authors.lastname: Strasser
authors.forename: D
authors.initials: D
authors.lastname: Metcalf
authors.forename: A G
authors.initials: AG
authors.lastname: Elefanty
mesh_terms: D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D002999:Clone Cells; D004305:Dose-Response Relationship, Drug; D016044:Fusion Proteins, bcr-abl / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology*; D015870:Gene Expression; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000473:pathology*; D007376:Interleukin-2 / Q000378:metabolism* / Q000494:pharmacology; D007377:Interleukin-3 / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008811:Mice, Inbred DBA; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D018631:ras Proteins / Q000378:metabolism
chemical_list: D007376:Interleukin-2; D007377:Interleukin-3; D019253:Proto-Oncogene Proteins c-bcl-2; D016044:Fusion Proteins, bcr-abl; D018631:ras Proteins